Project Summary This project investigates the functional changes in striatal neurons that develop in the chronic course of Parkinson's disease (PD) and largely involve the glutamatergic signaling. In PD, the loss of DA modulation in the striatum leads to significant changes in the function of striatal projection neurons (SPNs), which then play a key pathophysiological role in motor symptoms. The dysregulation of SPNs is evidenced by a significant amount of data including major morphological and physiological changes. In particular, SPNs are markedly hyperactive in animal models and patients with PD, and this upregulation is mediated by glutamatergic input from cortex and thalamus. However, the mechanisms underlying these changes are not fully understood, and the role of particular NMDAR and AMPAR signaling is not known. Here, we will profile thoroughly the SPN changes in advanced PD and determine the impact of NMDAR and AMPAR subunit components on pathological signaling. We take a novel approach using recently developed technologies for cellular identification in primate recordings and new pharmacological tools to test glutamate mechanisms with high selectivity. The ultimate goal of this project is to uncover and validate new therapeutic targets to improve motor functionality and help patients with PD. The project includes three specific aims. In the first aim, we will determine the abnormal activity pattern of identified SPN subtypes using optogenetics in the primate model of advanced PD that reproduces the full extent of the motor phenotype of the human disease. In the second aim, we will examine the regulation of expression of glutamate receptor subunits after dopamine loss in rodent and primates to determine the potential participation of subunits in the abnormal signaling. We will use rodent models for ex-vivo physiology with comprehensive analyses of behavioral paradigms and tests of subunit-selective inhibitors. In the third aim, we will take advantage of the extensive analysis of subunit roles to pinpoint the mechanisms that may account for functional SPN changes in the primate, and challenge them with the selected inhibitors directly in the striatum for physiologic and behavioral effects. This project employs diverse experimental approaches across multiple disciplines to address an important health problem, from the use of novel viral vectors and pharmacological agents, to the ex-vivo and in-vivo evaluation of identified neurons in rodent and primate PD models, to the final evaluations of pathophysiologic mechanisms in the parkinsonian primate. The data from these translational studies will be influential in the field, advance our understanding of pathophysiologic mechanisms, and catalyze the development of new therapeutic strategies in Parkinson's disease.